ABSTRACT
BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (HIRI) often occurs in liver surgery, such as partial hepatectomy and liver transplantation, in which myeloid macrophage-mediated inflammation plays a critical role. Cell division cycle 42 (Cdc42) regulates cell migration, cytoskeleton rearrangement, and cell polarity. In this study, we explore the role of myeloid Cdc42 in HIRI. METHODS: Mouse HIRI models were established with 1-hour ischemia followed by 12-hour reperfusion in myeloid Cdc42 knockout (Cdc42mye) and Cdc42flox mice. Myeloid-derived macrophages were traced with RosamTmG fluorescent reporter under LyzCre-mediated excision. The experiments for serum or hepatic enzymic activities, histologic and immunologic analysis, gene expressions, flow cytometry analysis, and cytokine antibody array were performed. RESULTS: Myeloid deletion of Cdc42 significantly alleviated hepatic damages with the reduction of hepatic necrosis and inflammation, and reserved hepatic functions following HIRI in mice. Myeloid Cdc42 deficiency suppressed the infiltration of myeloid macrophages, reduced the secretion of proinflammatory cytokines, restrained M1 polarization, and promoted M2 polarization of myeloid macrophages in livers. In addition, inactivation of Cdc42 promoted M2 polarization via suppressing the phosphorylation of STAT1 and promoting phosphorylation of STAT3 and STAT6 in myeloid macrophages. Furthermore, pretreatment with Cdc42 inhibitor, ML141, also protected mice from hepatic ischemia-reperfusion injury. CONCLUSIONS: Inhibition or deletion of myeloid Cdc42 protects liver from HIRI via restraining the infiltration of myeloid macrophages, suppressing proinflammatory response, and promoting M2 polarization in macrophages.
Subject(s)
Disease Models, Animal , Inflammation , Liver , Macrophages , Mice, Knockout , Reperfusion Injury , cdc42 GTP-Binding Protein , Animals , Reperfusion Injury/pathology , Reperfusion Injury/immunology , Reperfusion Injury/metabolism , Reperfusion Injury/genetics , Reperfusion Injury/prevention & control , cdc42 GTP-Binding Protein/metabolism , cdc42 GTP-Binding Protein/genetics , Mice , Macrophages/metabolism , Macrophages/immunology , Liver/pathology , Liver/metabolism , Liver/immunology , Inflammation/pathology , Inflammation/metabolism , Myeloid Cells/metabolism , Myeloid Cells/pathology , STAT3 Transcription Factor/metabolism , Male , STAT1 Transcription Factor/metabolism , Cytokines/metabolism , STAT6 Transcription Factor/metabolism , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/deficiency , Mice, Inbred C57BL , Gene DeletionABSTRACT
Castanopsis is diffusely spread in tropical and subtropical regions and is an important nectar source plant in China. The Castanopsis honey (CH) is characterized by its bitter taste. However, its composition and functions remain unclear. In this study, the physicochemical parameters, chemical composition, and antioxidant capacity of CH were comprehensively investigated, with the anti-inflammatory effects of the Castanopsis honey extract (CHE) evaluated based on the RAW 264.7 cell inflammatory model. The results revealed a high level of quality in CH based on the quality standards. Among a total of 84 compounds identified in CH, 5 high response compounds and 29 phenols were further quantified by UPLC-Q/TOF-MS. The high content of phenylethylamine (117.58 ± 64.81 mg kg-1) was identified as a potential marker of CH. Furthermore, the CH showed evident antioxidant activities, and the anti-inflammatory activities of CHE were observed to inhibit the release of nitric oxide (NO) and reduce the content of tumor necrosis factor alpha (TNF-α) and improve the content of interleukin-10 (IL-10) by regulating the NF-κB pathway. Our study indicates that CH has sound physicochemical properties and biological activities with a high level of quality, providing strong experimental evidence to support the further economic and agricultural development and application of CH.
